1. Field of the Invention
The invention relates to compositions and methods for the treatment of seizures and migraines.
2. Description of Related Art
The etiology of headaches, migraines, and most seizures has eluded prior art researchers. The novel etiology/pathogenesis provided in instant application ties all three together to a common underlying etiology. Novel etiology/pathogenesis based treatment methods for seizures and migraines are disclosed, versus prior art's symptom/observation based treatment methods.
Many prior art theories have been proposed, related to both migraines and seizures, however none have been able to account for all of the observed symptoms and diagnostic test results. Instant application provides a novel etiology and underlying pathogenesis which accounts for the disparate observations.
In summary, present invention discloses that oscillations in endocrine levels (e.g. estrogen, testosterone, prostaglandins, the active form of vitamin D, and others) alter the bone micro environment (i.e. osteoclast and/or osteoblast activity) in a manner the results in release of calcium (Ca2+) from the bone into the extracellular fluid, which in turn alters the nerve micro environment (via nerve membrane depolarization, enhanced neurotransmitter release at the synapse, and post tetanic potentiation) and alters the muscular micro environment (via enhanced neurotransmitter release at the neuromuscular junction and via enhanced muscular contractility). Any of the underlying endocrine oscillations mentioned above will result in the same pathogenesis and often multiple endocrine oscillations can occur simultaneously, contributing to the severity of the resulting migraine or seizure.
In contrast, prior art theories are based on localized observations, and as such cannot adequately explain the full spectrum of observed effects. Many different prior art theories exist.
Because it is estimated that two thirds of the world's 300 million migraine sufferers are women aged 15 to 55, suggesting estrogen plays a role, (Dodick and Gargus, “Why Migraines Strike”, Scientific American, August 2008, p. 58) a large part of the migraine discussion in this application is focused on comparing the novel pathogenesis presented under present invention to the large body or prior art work done on menstrual cycle related migraines. However, the same pathogenesis applies to seizures in people with low seizure thresholds as well as the same pathogenesis occurs in other endocrine—bone microenvironment mediated seizures and migraines.
Premenstrual Headaches: For purposes of present invention, premenstrual headaches are meant to loosely refer to the following set of symptoms, as described by one sufferer. The headache starts the day before the start of menstrual bleeding and lasts until the start of menstrual bleeding. The headache first manifests as a low level headache and ramps up over several hours into persistent, intense pain that in not at the very back or very front of the head and is accompanied by a hypersensitivity to sound. The headache may be accompanied by nausea and irritability. The sufferer prefers a dark, quiet room and going to sleep, as the headache is gone by the next morning at the start of menstruation.
Premenstrual Migraines: Premenstrual migraines are pulsating in nature, are often one sided, and may be more focused toward the front of the head. Migraines commonly occur before and during menstruation and may last from several hours to three days. Migraines have been associated with irritation of the trigeminal nerve (in the face), a spreading depolarization in brain, low serotonin levels in the brain, and vasoconstriction in the brain.
Premenstrual Headaches:
Prior art attention to premenstrual headaches is minimal, and prior art treatment methods are minimal. The entire Medscape article on managing premenstrual syndrome (Moline and Zendell, “Evaluating and Managing Premenstrual Syndrome”, 2000, Medscape) has only a single sentence relating to treatment of premenstrual headaches which reads: “Women with premenstrual headaches should try any of the common nonprescription analgesics (aspirin, acetaminophen, ibuprofen) at the onset of the headache.”
Premenstrual Migraines:
Prior art has given considerably more attention to premenstrual migraine headaches and numerous observations and theories about both migraines and premenstrual migraines exist.
One of the first theories to explain migraines was the classic theory of vasoconstriction/vasodilation—more specifically that migraines were caused by constriction of blood vessels in the brain, followed by dilation. Brain studies during migraine have shown that blood flow to the brain is abnormal.
The theory of hyper excitability built on the idea of vasoconstriction/vasodilation by adding that migraine sufferers were extra susceptible to normal triggers, such as stress. During periods of excitability, more calcium flows from extracellular fluid to intracellular space, resulting in vasoconstriction. This theory was bolstered by studies that calcium channel blockers could prevent migraine.
Irritation of the trigeminal nerve has also been implicated in migraines. Activation of the trigeminal nerve by compounds such as nitroglycerine or capsaicin triggers migraines, lending credence to the involvement of the trigeminal nerve in migraine headaches.
A spreading area of depolarization in the cortex has also been associated with migraines, which may begin 24 hours before an attack, with the onset of the headache occurring around the time of the largest area of the brain is depolarized.
Serotonin has also been implicated in migraines, as serotonin levels in the brain are low during migraines. This theory is bolstered by the fact that serotonin agonists, such as triptans, can provide pain relief.
Although no single theory exists under prior art to explain migraines, numerous treatments exist, that provide varying degrees of relief. Migraine medications include serotonin agonists, nonsteroidal anti-inflammatory drugs, combinations of over the counter pain killers, ergot alkaloids, corticosteroids, botox injections, opiate analgesics, lidocaine applied in the nasal cavities, magnesium, butterbur root, feverfew, riboflavin (vitamin B 2), coenzyme Q10, and S-adenosyl-L-methionine.
Menstrual migraines are more specifically tied to the ovulation cycle, and are triggered during declining estrogen levels, although some women are thought to suffer migraine from the progesterone decline.
A comprehensive synopsis of prior art work related to ovarian hormones and the pathogenesis of menstrual migraine is contained in the Martin and Behbehani article enclosed under IDS (Martin V T MD and Michael Behbehani, PhD, “Ovarian Hormones and Migraine Headache: Understanding Mechanisms and Pathogenesis—Part I”, © 2006 Blackwell Publishing, Medscape Jan. 26, 2006). Migraines are 3 times as common in women than in men and migraine attacks are commonly triggered by declines in serum estrogen levels. Accordingly, prior art menstrual migraine research is focused on ovarian hormone effects on A) serotonergic, B) noradrenergic, C) glutamatergic, D) GABAergic, and E) opiatergic systems, as disclosed in the article. The article then considers other possibilities, focusing on ovarian hormone effects on specific structures relevant to migraine headache such as meningeal arteries and the trigeminal nerve. A synopsis of the prior art synopsis is provided for reference:
A) Serotonergic. Serotonin 5-hydroxytryptamine; 5-HT) is a neurotransmitter that acts on seven distinct families of 5-HT receptors (5-HT1 to 5-HT7) and each receptor has multiple subtypes. Under prior art “Substantial evidence exists to suggest that the serotonergic system is important in the pathogenesis of migraine headache. A positron emission tomography (PET) study demonstrated increased serotonin synthesis capacity throughout all regions of the brain in migraine patients as compared to controls. Medications which are agonists of the 5HT1B, 5HT1D, and 5-HT1F receptors are efficacious abortive treatments for migraine headaches” (Martin and Behbehani).
Prior art has also demonstrated that estrogen effects serotonin by three pathways. First, estrogen treated monkey showed a nine-fold increase in tryptophan hydroxylase (TPH), the rate-limiting enzyme in synthesis of serotonin. Second, the serotonin reuptake transporter (SERT) removes serotonin from the synaptic cleft to terminate serotonergic transmission. Short term estrogen treatment of monkeys decreased amounts of SERT mRNA and longer treatments led to increased amounts of SERT mRNA. Third, monoamine oxidases, the primary enzymes that degrade serotonin, were reduced in monkeys receiving estrogen. Less compelling evidence suggests estrogen/progesterone combinations may modulate gene expression and binding potentials of serotonin receptors.
B) Noradrenergic System. The Martin and Behbehani article discloses that estrogen has been shown to up-regulate production of noradrenaline by up-regulating gene expression of tyrosine hydroxylase, a rate-limiting step in the production of noradrenaline. Studies also exist to show that estrogen may effect various subtypes of adrenoreceptors. The article also discloses that noradrenaline levels are decreased in migraineurs during headache free periods, suggestive of a state of chronic sympathetic hypofunction. Other studies imply that estrogen alone reduces central sympathetic activity, but the addition of progesterone may actually increase sympathetic tone.
C) Glutamatergic System. Glutamic acid is the major excitatory neurotransmitter in the central nervous system (CNS). The studies reviewed by Martin and Behbehani indicate that estrogen is a significant facilitator of the glutamatergic system and that certain effects can be attenuated by addition of progesterone.
D) GABAergic System: GABA is the major inhibitory neurotransmitter in the CNS. In vitro studies indicate that both estrogen and progesterone modulate GABAergic neurons. In vivo, women with premenstrual dysphoric disorder (PMDD) demonstrated increased cortical GABA during luteal phase (when both estrogen and progesterone levels are high) when compared to follicular phases (when estrogen is high but progesterone is low). The control group showed the opposite results with higher GABA levels in the follicular phases than the luteal phases.
E) Opiatergic System: The opiatergic system is important for pain control and regulation of reproductive behavior. Estrogen has been shown to increase levels of spinal cord enkephalin and enhance neuronal responsiveness of certain opioid receptors.
The article also covers other prior art theories by reviewing effects of ovarian hormones on specific structures relevant to migraine headaches.
Trigeminal Nerve: The trigeminal nerve is know to be involved in migraine headaches. The effects of ovarian hormones on the trigeminal nucleus caudalis (TNC) have been well studied. Animal model data show greater response magnitude and response duration of TNC neurons (i.e. enhanced sensitivity) is observed when estradiol and progesterone levels are high. It should be noted this is inconsistent with a premenstrual migraine, as falling levels of both hormones would predict reduced sensitivity of the TNC. However, TNC hypersensitization is consistent with falling estrogen levels under the novel etiology provided in present invention.
Brainstem Nuclei: The Martin and Behbehani article also postulate that ovarian steroids could potentially modulate neurotransmission within the brainstem nuclei to account for the increased blood flow to the dorsal pons observed on PET scans during spontaneous migraines.
Autonomic Nervous System: Estrogen alone reduces central sympathetic activity, reducing heart rate and sympathetic tone, while increasing parasympathetic tone. Addition of progesterone increases sympathetic tone. Chronic sympathetic hypofunction during headache-free period has been suggested in 10% to 15% of migraineurs.
Vascular Endothelium: Estrogen produces vasodilation through endothelium-dependent and non endothelial dependent mechanisms. The article suggests TNC sensitization by vasodilation of meningeal arteries.
Cortex: The anterior cingulate and insular cortices are activated on PET studies during a migraine attack. The article suggests ovarian steroids may modulate migraine on a cortical level.
Prostaglandin levels have also been associated with premenstrual/menstrual conditions, however, under prior art, the focus has been on the relation of prostaglandins and primary dysmenorrhea (menstrual cramping). Women with primary dysmenorrhea have increased activity of the uterine muscle with increased contractility and increased frequency of contractions. Cramping associated with dysmenorrhea usually begins a few hours before the start of bleeding and may continue for a few days. Prior art dysmenorrhea treatment methods center around prostaglandin inhibition. Prostaglandin levels have been found to be higher in women with severe menstrual pain than in women who experience mild or no menstrual pain. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis can provide relief and include drugs such as Naproxen, Ibuprofen, and Mefenamic Acid. However, many NSAIDs can cause gastrointestinal upset as a side effect and COX2 inhibitors are sometimes prescribed instead. Oral contraceptives are effective in preventing dysmenorrhea as they suppress ovulation and menstruation.
Seizures:
According to the Epilepsy Foundation, recurring seizures are generally a symptom of epilepsy and in about 70% of people with epilepsy, no cause can be found. In the remainder, causes include head injuries, brain damage from hypoxia at birth, brain tumors, lead poisoning, genetic conditions such as tuberous sclerosis, and infections such as meningitis or encephalitis. The intermittent burst of electrical activity are much more intense than usual and may occur in just one area of the brain (partial seizures) or may affect nerve cells throughout the brain (generalized seizures). Seizures are often associated with sudden and involuntary contraction of a group of muscles.
The “Seizure Threshold” concept holds that “everyone has a certain balance (probably genetically determined) between excitatory and inhibitory forces in the brain. The relative proportions of each determine whether a person has a low threshold for seizures (because of the higher excitatory balance) or a high threshold (because of the greater inhibition). According to this view, a low seizure threshold makes it easier for epilepsy to develop, and easier for someone to experience a single seizure.” (Epilepsy Foundation, http.//www.epilepsyfoundation.org/about/science/index.cfm, provided under IDS). Prior art anti-seizure medications work by modulating the balance between these excitatory and inhibitory forces in the brain.
Seizures, and the prior art drugs used to treat them, will be reviewed in light of the novel etiology/pathogenesis of present invention for consistency.